title: Mechanism of escape from nonsense-mediated mRNA decay of human beta-globin transcripts with nonsense mutations in the first exon.
abstract: The degradation of nonsense-mutated β-globin mRNA by nonsense-mediated mRNA decay (NMD) limits the synthesis of C-terminally truncated dominant negative β-globin chains and thus protects the majority of heterozygotes from symptomatic β-thalassemia. β-globin mRNAs with nonsense mutations in the first exon are known to bypass NMD, although current mechanistic models predict that such mutations should activate NMD. A systematic analysis of this enigma reveals that (1) β-globin exon 1 is bisected by a sharp border that separates NMD-activating from NMD-bypassing nonsense mutations and (2) the ability to bypass NMD depends on the ability to reinitiate translation at a downstream start codon. The data presented here thus reconcile the current mechanistic understanding of NMD with the observed failure of a class of nonsense mutations to activate this important mRNA quality-control pathway. Furthermore, our data uncover a reason why the position of a nonsense mutation alone does not suffice to predict the fate of the affected mRNA and its effect on protein expression.
authors.affiliation: Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Neu-Yilik
authors.forename: Beate
authors.initials: B
authors.lastname: Amthor
authors.forename: Niels H
authors.initials: NH
authors.lastname: Gehring
authors.forename: Sharif
authors.initials: S
authors.lastname: Bahri
authors.forename: Helena
authors.initials: H
authors.lastname: Paidassi
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Hentze
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kulozik
mesh_terms: D018389:Codon, Nonsense; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D020871:RNA Stability; D014158:Transcription, Genetic; D055544:beta-Globins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018389:Codon, Nonsense; D055544:beta-Globins